9/26/2016. Disclosures. Genitourinary Syndrome of Menopause: Novel Term for Common Conditions. Objectives ISSWSH NAMS CONSENSUS CONFERENCE

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1 Genitourinary Syndrome of Menopause: Disclosures Novel Term for Common Conditions Research, Consultant, and/or Speaker Risa Kagan, MD, FACOG, CCD, NCMP Clinical Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, UCSF East Bay Physicians Medical Group, Sutter Medical Foundation, Berkeley, CA Allergan, AMAG Pharma, Amgen Inc., Azure, FORE/American Bone Health, Heptares Therapeutics, Illumigyn, JDS Therapeutics, Juniper Pharma, Merck, Noven, Novo Nordisk, Own the Bone Advisory Board of the American Orthopedic Association, Palatin Technologies, Pfizer, Radius Health, Shionogi Inc., Sprout, Therapeutics MD, Valeant NAMS 2016 Objectives Historical review for the change in terminology, GSM vs. VVA Review incidence, signs, symptoms and pathophysiology of GSM ISSWSH NAMS CONSENSUS CONFERENCE Discuss the impact of GSM on quality of life from major surveys Review current therapeutic options for GSM Describe the Day -to -Day Impact of Vaginal Aging (DIVA) questionnaire MAY 17 19, 2013 Chicago, IL VVA,. 1

2 ISSWSH-NAMS Conference Objectives Components Used to Develop New Terminology Review basic and clinical science evidence on VVA and define key factors that influence diagnosis, treatment, and patient management Determine and develop a new/revised lexicon and nomenclature for VVA to enhance medical care, teaching and research Atrophy offensive and Vagina not for public use VVA- Vulva and Vagina, BUT what about the lower urinary tract Other examples: ED and OAB Generate an action plan to disseminate recommendations and raise awareness among members of the healthcare community and public Portman DH, May 2013,. Table 1.Portman DJ, Gass ML Menopause 2014;21: Publication and Sponsorship Strategy May 2013 ISSWSH-NAMS Conference Objectives Manuscript submission plan Success! Create a standardized, practical assessment tool clinicians can use to facilitate identification and staging of VVA (now called GSM) ISSWSH (ISSM, SMSNA) NAMS ASRM Endocrine Society Current ongoing project sponsored by NAMS, NERI, MGH and others, to develop new validated GSM PRO (patient reported outcome) instruments to use for research and clinical practice- STAY TUNED ACOG IMS AUGS Portman DJ

3 Genitourinary Syndrome of Menopause: GSM Differential Diagnosis Comprehensive term that includes symptomatic VVA as well as lower urinary tract symptoms related to low levels of estrogen and other sex steroids 1 Includes changes to the labia majora/minora, clitoris, vestibule/ introitus, vagina, urethra and bladder GSM is highly variable and women may present with all or few of the signs and symptoms of this condition Not attributable to another diagnosis Unlike the vasomotor symptoms of menopause, GSM symptoms may worsen over time unless treated 2 Symptoms are NOT limited to sexually active women 3 Candidiasis Bacterial vaginosis Desquamative inflammatory vaginitis Contact dermatitis (irritant or allergic) Lichen sclerosis Lichen planus Lichen simplex chronicus Vulvar intraepithelial neoplasm Vulvar cancer Other benign and malignant tumors Other medical disorder (e.g., diabetes, lupus) Psychological causes Trauma/Foreign body Vulvodynia 1.Portman DJ, Gass ML. Menopause 2014;21: Winneker RC, et al. Clin Pharmacol Ther 2011;89: Santoro N, Komi J. J Sex Med 2009;6: MacBride MB, Rhodes DJ, Shuster LT Mayo Clin Proc 2010;85(1):87 94 GSM Symptoms and Signs Menopause and ph Vaginal ph (lateral outer third of the vagina) is useful, effective, and inexpensive for screening for menopause The normal vaginal wall ph of a reproductive-aged woman is 3.8 to 4.5 ph > 5.0 is consistent with menopause - ph in the 5.0 to 6.5 range suggests either bacterial pathogens or decreased serum estradiol - In the absence of bacterial pathogens, a ph of is strongly suggestive of menopause Table 2.Portman DJ, Gass ML Menopause 2014;21: Caillouette JC, et al. Am J Obstet Gynecol 1997;176(6): ; discussion Moradan S, et al. Saudi Med J 2010;31(3):

4 Vaginal Maturation Index Vagina: Mature vs. Atrophic Postmenopausal vaginal epithelium: Superficial cells decreased Parabasal cells increased Premenopause Postmenopause Superficial cells 15% 1% Intermediate cells 80% 60% Parabasal cells 5% 39% Premenopausal Erectile tissue Folds or rugae Muscular coat Inner mucous lining contains large amount glycogen Postmenopausal Vagina Loss of folds Loss of inner mucous lining and glandular function Freedman M. Menopause Manag. 2008;17:9-13 Samsioe G, A profile of the Menopause 1995; 49 (Fig. 6.4) Vaginal Histology Overview of GSM Premenopause Epithelium well-estrogenized,multilayered with good blood supply, superficial cells rich in glycogen Postmenopause Estrogen-deficiency atrophy with marked thinning of epithelium, blood supply reduced, and loss of glycogen Women have an increase in life expectancy. By 2020, there will be more than 50 million women in the U.S older than 51 years 1 GSM symptoms will affect at least 50% of postmenopausal women at some point in their lives Prevalence increases with menopausal stage: - 4% during perimenopausal transition and 47% 3 years post FMP 2 GSM: chronic, progressive, and symptoms do not improve without treatment Many women remain unaware that vulvar and vaginal changes can be a direct result of the menopausal transition Communication challenges/barriers exist for both HCPs and patients Significant under-diagnosis, under-treatment or delays in seeking treatment HCP, health care provider 1.NAMS, Menopause Practice: A Clinician s Guide. 5 th edition Portman DJ, Gass ML Menopause 2014;21: Sturdee DW, Panay N. Climacteric 2010;13:

5 REal Women s VIews of Treatment Options for Menopausal Vaginal ChangEs (REVIVE survey) Largest US survey: 3,046 postmenopausal women (45-75yrs) with VVA symptoms- dryness, dyspareunia, irritation 44% never discussed VVA symptoms with an HCP Only 13% stated an HCP initiated the VVA conversation 40% expected the HCP to initiate the conversation 24% of women attributed VVA symptoms due to menopause. If aware natural part of aging 19% of HCPs addressed their sexual lives VVA affected sex, sleep, enjoyment of life and temperament Kingsberg S, Wysocki S, Magnus L, Krychman M. J. Sex Med Jul;10(7) Vaginal Health: Insights, Views & Attitudes (VIVA) Online international questionnaire 3520 postmenopausal women, aged years 45% reported vaginal discomfort: (only 4% knew this was VVA) 83% vaginal dryness & 42% pain during intercourse 75% of women felt that vaginal atrophy would have negative impact on life: When asked how do they think vaginal discomfort affects women s lives in general: 65% negative consequences on sex life 40% negative consequences on marriage/relationship 36% lowers quality of life 31% makes them feel old 26% negative impact on self-esteem 13% negative impact on social life Nappi RE, Kokot-kierepa M. Climacteric 2012;15(1):36-44 Women s Voices in the Menopause International computer-assisted web interviews on vaginal atrophy 4246 postmenopausal women, aged years 5 countries (US, Canada, Finland, Sweden, UK) Of women who had been prescribed treatment for menopause-related vaginal discomfort: Vulvovaginal Atrophy Strongly Associated with Female Sexual Dysfunction Menopause Epidemiology Study cross-sectional, population-based study 1480 sexually active postmenopausal US women aged years Prevalence of VVA: 57% Women with FSD were 3.8 (CI ) times more likely to have VVA than women without FSD 67% reported positive effects: 28% improvements in everyday life 27% sex life returning to normal 26% better quality of life Premenopause Postmenopause Nappi RE, Kokot-Kierepa M. Maturitas 2010; 67(3): FSD, female sexual dysfunction Levine K, et al. Menopause 2008; 15:661 5

6 Therapeutic Options Vaginal Lubricants and Moisturizers FDA APPROVED AS COSMETICS Nonmedical - Regular Sexual Activity Nonprescription therapies OTC lubricants and moisturizers Herbal products Prescription therapies Systemic estrogen Local low -dose vaginal estrogen Ospemifene Approval process less rigorous Data often limited, few studies Lack of scientific trials for determining efficacy, safety and side effects. Courtesy of Susan Kellog Spadt, PhD, CFNP, IF Lubricants and Moisturizers Herbal Products Lubricants are considered for short-term relief of vaginal dryness during sexual activity Short duration of action Must be applied frequently Sexual aid Vaginal moisturizers are considered for long-term relief of vaginal dryness Continuous use; several times a week Everyday aid The Herbal ALTernatives for Menopause Study (HALT) Randomized, double blind, placebo 1 year trial 351 women, high retention for all regimens Dietary supplements: - Black Cohosh, other herbs, soy No beneficial effect on VVA as compared to placebo Sturber C, et al. Curr Probl Dermatol 2011, vol 40 pp Reed, Newton, et al, Menopause 2008; 15:

7 Prescription Therapies FDA January 2003 guidelines for vulvar and vaginal studies for VVA assessment FDA Approved Investigational and Off Label 3 co-primary endpoints Cytological (maturation index-parabasal and superficial cells) Vaginal ph Severity of patient-assessed MBS MBS, most bothersome symptoms; VVA, vulvovaginal atrophy. US Department of HHS, FDA, Center for Drug Evaluation and Research. Guidance for Industry. FDA guidance: Assessment of VVA Estrogen Treatment and VVA MBS Patient-assessed symptom at baseline - Vaginal dryness - Pain with intercourse - Itching/irritation - Bleeding associated with sexual activity - Soreness Rated on a 3 or 4 point scale (none, mild, moderate, severe) One symptom rated as moderate or severe and followed until the end of study Estrogen lowers vaginal ph, increases subepithelial capillary growth, thickens epithelium Raises level of vaginal secretions VMI increases reflecting higher percentage of superficial cells relative to parabasal cells Estrogen therapy alleviates subjective vaginal symptoms Dryness, soreness, irritation, pruritus, and dyspareunia US Department of HHS, FDA, Center for Drug Evaluation and Research. Guidance for Industry. VVA, vulvovaginal atrophy. Archer DF. Menopause 2010;17:

8 Schematic depiction of the effects of estrogen on the vaginal epithelium Systemic Estrogen Therapy Menopausal symptoms Prevent Bone loss VVA 10%-15% of women on systemic HT for symptoms may also need local low -dose estrogen therapy1 Approved lower systemic doses may lack efficacy Risks/benefits see MenoPro App Archer DF. Menopause 2010;17: NAMS Position Statement. Menopause 2013;20(9): Low-Dose Vaginal Estrogen Therapy Vaginal Estrogen Therapy Preferred to systemic ET if GSM symptoms are the main complaint Cochrane review of 30 efficacy trials, 6,235 women--all local estrogen products tested alleviate symptoms of VVA with similar efficacy (2016) Thin atrophic vaginal epithelium absorbs locally applied estrogen faster than after the epithelium has been estrogenized important to use as studied A progestogen is generally not indicated, but only 1 year safety data Elimination of first-pass effect by hepatic enzymes may account for reduced risks of adverse events including thrombosis (local and lower doses) Recent ACOG committee opinion endorsed for use in breast cancer survivors Use if unresponsive to non-hormonal remedies NAMS Position Statement. Menopause 2013;20(9): Archer DF. Menopause 2010;17: ACOG Committee Opinion 659, March 2016 Lethaby A, Ayeleke R, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database of Systematic Reviews 2016, Issue 8, CD Low-dose vaginal estrogen except for Femring a Table 2: NAMS Position Statement. Menopause 2013;20(9):

9 Onset of Action of Vaginal Estrogens Ospemifene Improvements in VMI reported as early as 2 to 4 weeks after initiation of vaginal CEE cream or estradiol vaginal tablets Vaginal ph falls to lowest levels by 3rd week of vaginal estrogen treatment (number of superficial cells in the vagina has already increased by that time) Superficial cells continue to increase during 12-weeks of therapy Ospemifene is the only SERM approved for the treatment of moderate to severe dyspareunia a symptom of vulvovaginal atrophy due to menopause.(february 2013) Daily 60mg oral tablet Two 12 -week efficacy clinical trials that met all co-primary endpoints A 52-week efficacy and safety extension study showed sustained improvements and no VTE, endometrial hyperplasia or carcinoma VMS were the most common AE 7.2% vs 2% in placebo Preclinical data reveal antiestrogen effects on breast tissue and agonistic effects on bone Current ongoing Phase 3 trial with primary endpoint of vaginal dryness Bachmann GA, Komi JO. Menopause 2010;17: CEE, conjugated equine estrogen. Santen RJ, Pinkerton JV, Conaway M, et al.menopause 2002;9: Portman DJ, Bachman GA, Simon JA. Menopause 2013;20: Simon JA, Lin VH et al., Menopause 2013;20: Investigational and Off-Label Therapies TX-004HR estradiol vaginal softgel capsule -- Therapeutics MD Generic estradiol vaginal tablet, 10 mcg-- Amneal Intravaginal DHEA -- EndoCeutics Lasofoxifene oral systemic -- Sermonix Lasofoxifene local vaginal -- Azure Testosterone Vaginal Cream (U.S. pilot studies breast cancer patients) often used compounded in US Estriol Vaginal Gel/Pessaries -- (Europe) Vaginal Oxytocin (vagitocin) -- (Europe) Fractional CO2 Laser Treatments Day-to Day Impact of Vaginal Aging Questionnaire (DIVA) Multidimentional self-report questionnaire: 23 items in 4 domain scales 1. activities of daily living 2. emotional well-being 3. sexual functioning 4. self-concept and body image Designed to facilitate evaluation of the impact of GSM symptoms on QOL for women of diverse backgrounds Valid for researchers and clinicians Huang AJ, Gregorich SE, et al. Menopause 2015;22(2):